Precocious puberty, adiposity, and gonadotropin-releasing hormone agonists: Is the hen chasing the egg or vice versa?

Precocious puberty, defined as the onset of secondary sexual characteristics (breast development) before the age of 8 in girls, is a condition with significant medical, psychological, and social implications.^[1] The premature activation of the hypothalamic–pituitary–gonadal (HPG) axis can lead to accelerated bone maturation, early menarche, reduced adult height, and increased emotional stress during childhood.^[2] The incidence of central precocious puberty (CPP) is rising worldwide, with the onset of Tanner stage 2 advancing by approximately 3 months per decade.^[3] Over recent decades, treatment with gonadotropin-releasing hormone (GnRH) analogs has become the standard of care for managing CPP. The primary objective of this therapy is to halt pubertal progression and optimize adult height.^[4]

While the efficacy of GnRH analogs (GnRHa) in suppressing the HPG axis is well established, their short- and long-term effects on anthropometric parameters — particularly height velocity, body mass index (BMI), and body composition — remain a subject of ongoing research, with published data often showing contradictory results.^[5]

Given the global rise in pediatric obesity, it is increasingly important to understand how GnRHa therapy may affect growth patterns and metabolic profiles across diverse populations. In this context, the study by Hulse et al. provides valuable insights into the evolving anthropometric profiles of girls undergoing GnRHa therapy and offers an opportunity to re-examine these findings from a broader perspective.^[6] In this retrospective analysis, data from 80 girls with idiopathic CPP, treated at a mean age of 8.1 years for an average duration of 2.6 years, were analyzed. The main findings were, first, a significant decrease in height velocity at years 2 and 3 of treatment compared to year 1, leading to a reduction in height standard deviation score (SDS) from 1.5 ± 1.2 SDS at baseline to 0.5 ± 1.7 SDS by year 3. Notably, individual growth velocity data are presented, showing that some patients virtually stopped growing by the 2^nd and 3^rd years. The second key finding was a late increase in BMI SDS, from 0.8 ± 0.9 SDS at treatment initiation to 1.3 ± 0.7 SDS at completion. Consequently, the proportion of overweight or obese children increased from 61% to 76% during therapy. Unfortunately, only 34 patients completed treatment, reducing the statistical power for long-term outcome analysis and introducing bias. Interestingly, this cohort appears older and more advanced in puberty than those typically seen in European or American series, with 20% of girls having already experienced menarche at baseline. This may complicate the interpretation of height velocity changes during treatment but also add valuable data from a non-Caucasian population.

This study enhances our knowledge and highlights the challenges associated with using GnRHa for treating precocious puberty. Concerning height, the basic therapeutic principle in increasing height is to reduce growth velocity while further slowing bone age maturation and preserving growth potential. It is well established that the effectiveness of this approach is limited and depends on the age at pubertal onset,^[7] with much better outcomes observed in children with early-onset CPP and with starting the treatment early.^[4] However, when children stop growing on treatment, no beneficial effect on height can be expected, a finding reminiscent of the results of GnRH agonist treatments in children with normally timed puberty.^[8]

Regarding adiposity and BMI, 20 years ago, Paterson et al. reported a similar increase in BMI during GnRHa therapy, with mean BMI SDS rising from 0.9 to 1.2 in CPP patients.^[9] Since then, several studies have addressed this point with conflicting results. Yoon et al.^[10] found no significant change in BMI z-score in 127 Korean girls with CPP, whereas another Korean study did report a significant increase in BMI z-score after 18 months of treatment.^[11] A recent meta-analysis of 28 studies found that BMI SDS at adult height, after cessation of GnRH agonist treatment, was similar to baseline BMI SDS, after a transient increase during treatment.^[12] However, the jury is probably still out on this, with genetic and individual susceptibilities likely acting as important confounding factors. Moreover, baseline characteristics of the patient population may further influence outcomes, as BMI SDS at the start of treatment appears to be a significant modifier.^[11,13]

In Hulse’s^[6] study, 61% of treated patients were overweight or obese at baseline, compared to 8.4% and 12.4% of Indian children in the general population.^[14] The increased prevalence of obesity in CPP is well documented and adiposity is recognized as a key factor controlling pubertal onset, both at the phenotypic and at the genetic level.^[15] Aghaee et al. reported a dose-response relationship between BMI and the age at pubertal onset in both sexes.^[16] Therefore, the relationship between adiposity and precocious puberty represents a typical “chicken and egg” dilemma: Increased adiposity is a major risk factor for precocious puberty, while suppression of the gonadotropic axis and the resulting reduction in sex steroid hormones tends to promote fat mass accumulation, especially in those who are genetically predisposed to it. Theoretically, resumption of a normal HPG axis function after treatment should restore the pre-treatment metabolic state. This complex interplay makes it difficult to determine whether CPP or early menarche independently increases long-term metabolic and cardiovascular risk.^[17]

Altogether, the findings by Hulse and Rai remind us that treatment with GnRH agonists should be part of a holistic approach to managing adolescents with CPP, including psychological support, nutritional support to prevent weight gain, and ensuring adequate calcium and vitamin D intake for optimal bone health.^[6] For instance, a recent Korean study found a significant correlation between post-treatment height gain and BMI: Girls whose Δ height from cessation to menarche was higher (≥9.79 cm) had significantly lower BMI at diagnosis, treatment discontinuation, and menarche.^[18]

Further long-term studies are required to disentangle the effects of weight trajectories, HPG axis activation, and treatment effects in patients with CPP. A differential metabolic response based on baseline weight status and sex remains underexplored and should constitute future research goals to develop individualized weight management strategies during GnRHa therapy.